Anti-amnesic effect of neurosteroid PREGS in Aβ25-35-injected mice through σ1 receptor- and α7nAChR-mediated neuroprotection.

A single intracerebroventricular injection of β-amyloid 25-35 peptide (Aβ(25-35)) (9 nmol/mouse) induces the spatial cognitive deterioration and approximately 50% loss of pyramidal cells in hippocampal CA1 region within 1 week. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (σ(1)R) and α7 nicotinic acetylcholine receptor (α7nAChR), on the cognitive deficits and the death of pyramidal cells in Aβ(25-35)-mice. Herein, we reported that the administration of PREGS (1-100 mg/kg) for 7 days after Aβ(25-35)-injection could dose-dependently ameliorate the cognitive deficits and attenuate the apoptosis of pyramidal cells. Either the σ(1)R antagonist NE100 or the α7nAChR antagonist MLA could block the neuroprotection of PREGS in Aβ(25-35)-mice. Both the σ(1)R agonist PRE084 and the α7nAChR agonist DMXB could mimic the PREGS-neuroprotection against the Aβ(25-35)-neurotoxicity. The neuroprotection of PRE084 was attenuated by MLA, but the DMXB-action was insensitive to NE100. The neuroprotection of PREGS, PRE084 or DMXB was blocked by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, whereas only the effect of PREGS or PRE084 was sensitive to the MAPK/ERK kinase (MEK) inhibitor U0126. PREGS prevented Aβ(25-35)-inhibited Akt (Serine/threonine kinase) phosphorylation leading to increase in caspase-3 activity, which was σ(1)R- and α7nAChR-dependent. By contrast, PREGS-rescued reduction of extracellular signal-related kinase-2 (ERK2) phosphorylation in Aβ(25-35)-mice only required the activation of σ(1)R. Blockage of PREGS-neuroprotection by LY294002 significantly attenuated its anti-amnesic effect in Aβ(25-35)-mice. The findings indicate that the anti-amnesic effects of PREGS in Aβ(25-35)-mice depend on the σ(1)R- and α7nAChR-mediated neuroprotection.